7-cyano-hexahydro pleiadenes

ABSTRACT

Hexahydro pleiadenes substituted at the seven position, e.g., 1,2,3,7,12,12a-hexahydro-7-carboxamido pleiadene, and dibenzoheptalenes substituted at the 8-position, e.g., 1,2,3,4tetrahydro-8-(1-methyl-4-piperidyl)-8H-dibenzo(b,ef)heptalene, prepared from corresponding 7-substituted-hexahydro pleiadenes and 8-substituted dibenzoheptalenes, are useful as anticonvulsants.

United States Patent [191 Houlihan et a1.

[ 7-CYANO-HEXAHYDRO PLEIADENES [75] Inventors: William J. Houlihan, Baden,

Austria; Jeffrey Nadelson, Parsippany, NJ.

[73] Assignee: Sandoz, Inc., E. Hanover, NJ.

[22] Filed: June 12, 1973 [21] Appl. No.: 369,208

Related US. Application Data [62] Division of Ser. No. 172,587, Aug. 17, 1971, Pat. No.

[52] US. Cl...... 260/465 R; 260/465 F; 260/465 G; 260/515 A; 260/515 R; 260/520; 260/553 A; 260/558 R; 260/559 R; 260/566 A;

260/570.5 CA; 260/611 F; 260/618 F;

[51] Int. Cl. C07c 121/64 [58] Field of Search 260/465 R, 465 G, 465 F [56] References Cited UNITED STATES PATENTS 3,242,212 3/1966 Davis et al. 260/465 X [111 3,888,900 June 10, 1975 OTHER PUBLICATIONS Craig: Chemical Abstracts, Vol. 64, pp. 8106-8107 (1966).

Primary Examiner-Lewis Gotts Assistant ExaminerDo1ph H. Torrence Attorney, Agent, or Firm-Gerald D. Sharkin; Robert S. l-Ionor 5 7] ABSTRACT 2 Claims, No Drawings 1 7-CYANO-HEXAHYDRO PLEIADENES This is a division of application Ser. No. 172,587, filed Aug. 17, 1971, now US. Pat. No. 3,763,233 dated Oct. 2, 1973. 5

This invention relates to pleiadenes substituted at the 7-position and dibenzoheptalenes substituted at the 8- position. Moreover, the invention concerns intermediates and pharmaceutically acceptable salts of said compounds, and processes therefor.

The compounds of this invention may be represented by the following structural formula:

O H -NHC-NHR NH or CONT-l wherein R represents lower straight chain alkyl having l-4 carbon atoms, e. g., methyl, ethyl and butyl. Compounds of formula I in which R represent the group ff .4. NHC-NHR are prepared according to the following reaction scheme:

where R, R R and n are as previously defined.

This process may be carried out by treating a compound of the formula lb with a compound of the formula (II) in a suitable inert organic solvent. Although the particular solvent used is not critical, hydrocarbon solvents such as benzene, toluene, Xylene and ethers such as tetrahydrofuran or diethyl ether may be used, especially diethyl ether. The reaction temperature is about 080C., preferably 20 to 30C., although the temperature is not crtical. The reaction time may vary widely and is usually in the range of 1-24 hours.

Compounds of the formula lb are prepared according to the following reaction scheme:

(Ib) l wherein R, R and n are as previously defined.

This process may be carried out by reducing a compound of the formula III in the presence of an inert organic solvent. The reducing agent used can be any of the standard reducing agents, in particular, an alkali metal alkanol especially a sodium metal ethanol. Although, the particular solvent used is not critical, the lower alkanols are preferred, e.g., methanol, propanol,

and ethanol, the latter being preferred. The reaction may be carried out at a temperature of about 50150C., preferably at the reflux temperature of the reaction mixture. The reaction time may vary widely I preferably.

and depends upon rate of sodium addition, from 1 to 3 hours. Y

Compounds of the formula III are prepared according' to the following reaction scheme:

NH OH- B3 (ICII) wherein R, R and n are as previously defined.

3 4 This process may be carried out by treati a kaline earth metal hydroxide or hydrides, e.g., sodium pound of the formula V with a compound of the forhydroxide, potassium hydroxide, calcium hydroxide or mula IV or an acid additon salt thereof in a suitable sodium hydride n aqueous r l holic solv n h inert organic solvent. Although the particuar solvent as lower alkanols, methanol, ethanol, p p used is not critical, hydrocarbon solvents such as benand the like, of mlXlllreS thereof, at about to zene, toluene, xylene and pyridines may be em l d, 180C, preferably 70-lOOC., for about 12-48 hours.

the latter being preferred. The reaction temperature is The resulting product may then be treated in the above about 80-180C., preferably at the reflux temperature solvent with strong mineral acid such as hydrohalic of the reaction mixture. The time of reaction may be acid, -g-, hydrochloric acid or ydr r mi d, or from to 48 hours. 10 sulfuric acid, phosphoric acid and the like, at a temper- Compounds of the formula V are prepared according ature of from about 10 to 15C., preferably 5 to to the following reaction scheme: 1 10C. The time and temperature of'the reaction and the l R R2 0 fi (v1) (v) o where R, R and n are as previously defined. particular solvent utilized is not critical. The resulting d v b d b compound VIII and IX may be separated using conven- Compoun S may e prepare y trea comtional techniques. Compounds VIII and IX, together or pounds VI with Slrong ineral acld sulfuric i separately, may be converted to the acids of formula VI fgl i fggy g g g a 30 by reduction. Accordingly, compounds VI may be obio l C l fo r about l 5 h i i i s. Although ssl senl is not taingi by treating compounds vm or Ix wtih hydrogen considered necessary, solvents which may be used ini i zg sollvents such l s; alkanols 'i, clude aromatic or aliphatic hydrocarbons, e.g., beng g sg g i fi d gg ga z zene toluene pemine and the like The temlperatures 35 droch loric acid or hydrobromi c acid or sulfuric r aci d solvents and 0 reactlon are no crmca and the like, over palladium catalyst, preferably 5 to 30 The compounds VI are obtainable according to the percent palladium on carbn, conveniently IOpercent following multi-step reaction scheme: Pd/C at a temperature of 80C., preferably HO-(i wherein R R and n are as previously defined, and R 35C., and a pressure of about -100 psi for represents lower alkyl, i.e., alkyl of l-4 carbon atoms, about 2-4 hours. The pressure, temperatures time of e.g., methyl or ethyl. reaction'and particular solvent utilized are not critical.

Compounds VII provide compounds VIII and IX Compounds VII may be prepared according to the when treated first with strong base such as alkali or alfollowing reaction scheme:

. on R Lv 2\ R (CH) 2 n 5 R N c o wherein R R R and n are as previously defined.

Compounds VII may be prepared by condensing a compound X with a compound XI in an inert atmo- XIII sphere, e.g., nitrogen gas, and in an inert solvent such as ether, e.g., diethyl ether or tetrahydrofuran, or hydrocarbons or aromatic hydrocarbons such as hexane, heptane, benzene, toluene and the like and subjecting the reaction mixture to hydrolysis, preferably with water at about to 10C. The condensation may be carried out at a temperature of from about 60 to C., preferably about-C. for about 1 to 3 hours. The exact time and temperature of reaction and the particular solvent used is not critical in obtaining the product VII.

' bly from to C. The reaction time may vary widely and is usually in the range of 5-45 minutes. However, the temperatures, solvents and time of reactin are not critical.

Compounds of the formula XIII are prepared accord- It will be understood that certain of the compounds 40 ing to the following reactionscher'ne:

(XIII) wherein R, R and n are as previously defined.

This process may be carried out by treating a compound' of the formula XV with silver cyanide in a suit- 5 able inert organic solvent. Although the particular solvent used is not critical, hydrocarbon solvents such as benzene, toluene, xylene are preferred, especially benzene. The reaction temperature is from 50 to C., preferably at the reflux temperature of the reaction mixture. The time may vary widely and is usually in the range of 2 to 24 hours. The time and temperature of the reaction are not critical.

Compounds of the formula XV are prepared accord- 5 ing to the following reaction scheme:

. CH 5 R1 l 01 I I 2 2 R i (in Cl XVI I wherein R, R and n are as previously defined.-

This process may be carried out by treateing a compound of the formula XVII with a halogenating agent, e.g., sulfonyl chloride, phosphorus pentachloride, especially gaseous hydrochloric acid in a suitable organic solvent. Although the particular solvent used is not critical, hydrocarbon solvents such as benzene, toluene, xylene and ethers such as tetrahydrofuran or diethyl ether are preferred, especially benzene. The reaction temperature is from about to 80C., preferably from about 20 to 30C. The time may vary widely and usually is in the range of to 45 minutes.

Compounds of the formula XVII are prepared according to the following reaction scheme:

nol, the latter being preferred. The reaction temperature is from about 0 to 80C., preferably to C. The reaction time may vary widely and is usually from about 1 to 24 hours.

All of the above-mentioned compoundsmay be recovered using conventional techniques, e.g., filtration or recrystallization. It will be understood that certain of the compounds of formulas I, la, lb, Ill, V, VI, VII, VIII,

IX, XIII, Ic, XV, and XVII exist in racemic form or in the form of optically active isomers. The separation "and recovery of respective isomers may be readily accomplished employing conventional techniques and such isomers are included within the scope of the invention.

The compounds of the formula I are useful because they possess pharmacological activity in animals. More particularly, the compounds possess anti-convulsant activity as indicated by their activityin mice given 131.9 mg/kg of body weight of active material and tested using the method basically as described by'Orloff et al. (Proc. Soc. Exp. Biol. 70: 254, i949) respecting chemically induced seizures.

For such use, compounds of the formula I may be combined with a pharmaceutically acceptable carrier or adjuvant, and may be administered orally in such forms as tablets, capsules, elixirs, suspensions and the or suspension. The dosage will vary depending upon the mode of administration utilized and the particular compound employed.

The compounds of the formula I may be suitably administered in the form of their non-toxic pharmaceutically acceptable acid addition salts. Such salts possess the same order of activity as the free base, and are readily prepared by reacting the base with an appropri: ate acid and accordingly are included within the scope of the invention. Representative of such salts are the mineral acid salts, such as the hydrochloride, hydrobromide, sulfate, phosphate and the like and the organic acid salts, such as the maleate, fumarate, tartrate, cit.-- rate, succinate, benzoate, acetate, p-toluenesulfonate,

XVII

tered at a daily dosage of from about 1-200 milligrams per kilogram of animal body weight. The daily dosage is preferably given in divided doses, e.g., 2 to 4 times a day, or in sustained release form. For most large animals, the total daily dosage is from about 75 to 2000 milligrams and dosage forms suitable for internal administration comprise from about 20 to 1000 milligrams of the compound in admixture with a solid or liquid pharmaceutical carrier or diluent.

As previously noted, the compounds of formula I exist as optical isomers. In some cases greater pharmacological activity or other beneficial attributes may be found for a particular isomer and in such cases administration of such isomer may be preferred.

Tablets and capsules containing the ingredients indicated below may be prepared by conventional techniques and are useful in the treatmen of convulsants at like or parenterally in the form of an injectable solution Ingredients Weight (mg) Tablet Capsule 1,2,3 ,7, l 2,] 2a-l-Iexahydro-7- carboxamido pleiadene 250 250 tragacanth l0 lactose 197.5 250 I corn starch 25 talcum l5 magnesium stearate 2.5

The following pharmaceutical compositions are formulated with the indicated amount of active agent using conventional techniques. The injectable solution lnjectable Liquid Ingredients (Weight (Weight l,2,3,7, l2,12a-hexahydro-7- carboxamido pleiadene 0.5 to 3.5 sodium alginate 0.5 sodium benzoate 0.1 to 0.5 Simple syrup 30 to 70 lecithin 0.5 sodium chloride as desired flavor as desired color as desired sorbitol solution 70% US? 10 to 30 buffer agent to adjust pH as desired as desired for desired stability water to desired to desired volume volume EXAMPLE 1 a-( 1 ,2,3 ,4-tetrahydro-1 hydroxyl -naphthyl)-N-methyl-o-toluamide To a flask equipped with a stirrer, dropping funnel, condenser and gas inlet tube maintained under a nitrofiltered and evaporated to provide crude 3,4-

gen atmosphere, there is added at room temperature 40.0 g. (0.28 mole) of o-methyl-N-methyl-benzamide and 250 ml. of anhydrous tetrahydrofuran The reaction flask is immersed in an ice bath and cooled to an internal temperature of 5C. Stirring is initiated and 380 ml. of 1.6 n-butyllithium (0.616 mole) in hexane is added dropwise in ca 1 hours while maintaining the temperature below 8C. The resulting red dilithio saltis stirred at 5C. for one additional hour and then the reaction flask is immersed in a dry-ice acetone bath and cooled to an internal temperature of --60C. To the cold reaction mixture 21 solution of 41.0 g. (0.28 mole) of 3,4- dihydro-l (2H)-naphthalenone in 140 ml. anhydrous tetrahydrofuran is added dropwise in ca 45 minutes maintaining the temperature between -60C. and 50C. The resulting reaction mixture is stirred at 60C. for 1 hour, allowed to warm to 0C. ca 1 hour and then treated with 200 ml. of water while maintaining the temperature below 10C. The resulting solid is washed thoroughly with water and dried to give oz-( 1,2- ,3 ,4-tetrahydro- 1 hydroxyl -naphthyl)-N-methyl-otoluamide; m.p. 204-206C.

' EXAMPLE 2 a-( 1,2,3 ,4-tetrahydro- 1 hydroxyl naphthyl )-o-toluic acid and 3 ',4'-dihydrospiro[isochroman-3 ,l 2'H )naphthalen 1 one dihydrospiro[isochroman-3 ,1 2'H )naphthalen]- l-one.

EXAMPLE 3 a 1 ,2,3,4-Tetrahydro-l-naphthyl)-o-toluic acid A mixture of 30 g. (0.106 mole) of a-(l,2,3,4- tetrahydro-l-hydroxy-l-naphthyl)-o-toluic acid and 30 g. (0.114 mole) 3,4-dihydrospiro[isochroman-3,l (2'H)-naphthalen]-1-one is dissolved in 1 liter of ethanol containing 18.1 g. of 10 percent palladium on carbon (Pd/C) and 9.5 ml. of concentrated hydrochloric acid. The resulting mixture is hydrogenated at psi and 25C. on a Parr apparatus until no further hydrogen is absorbed. The mixture is filtered to remove the catalyst and evaporated in vacuo. The residue is dissolved in methylene chloride, washed once with 200 ml. of water, dried over magnesium sulfate, filtered and evaporated to yield a-( l,2,3,4-tetrahydro-l-naphthyl)- o-toluic acid; m.p. 103-l0 7C.

EXAMPLE 4 l ,2,3 ,12a-Tetrahyro-7( l 2H)-pleiadenone To a flask equipped with a stirrer, dropping funnel, condenser and gas inlet tube maintained under a nitrogen atmosphere there is added at room temperature 10.6 g. (0.04 mole) of a-(l,2,3,4-tetrahydro-1naphthyl)-o-toluic acid and 100 ml. of anhydrous benzene.

Stirring is initiated and 8.3 g. (0.04 mole) phosphorous pentachloride is added portionwise maintaining the 'hours at room temperature. The layers are separated and the aqueous phase is washed once with 100 ml. benzene. The combined organic phases are washed with 100 ml. of water, 50 ml. of 10 percent sodium carbonate, 50 ml. of water and 50 ml. of saturated sodium chloride solution. They are then dried over magnesiumsulfate, filtered and evaporated to give l,2,3,12atetrahydro-7(12H)-pleiadenone; m.p. 6468C.

, EXAMPLE 5 l,2,3,7,l2,12a-Hexahydro-7-oximino pleiadene 8 A mixture of 33 g. l,2,3,l2a-tetrahydro-7(12H)- pleiadenone (0.133'm0le) and 33 g. hydroxylamine hydrochloride (0.47 mole) and 500 ml. pyridine is heated under reflux for 19 hours. The solution is allowed to cool and the solvent is evaporated in vacuo, the residue is then dissolved in chloroform, washed with water and heated at reflux for 48 hours and cooled to an internal temperature of 0C. Concentrated hydrochloric acid is added, maintaining the temperature below 20C. until pH 2 is obtained. The resulting precipitate is filtered and washed thoroughly with ethanol, then with water, and dried to provide a-(l,2,3,4-tetrahydro-lhydroxyl-naphthyl)-o-toluic acid, m.p. 132l33C. The ethanolic filtrates are concentrated in vacuo and the residue dissolved in methylene chloride and washed twice with 200 ml. of water, dried over magnesium sulfate,

from ethanol to give then with sodium chloride, dried over magnesium sulfate and evaporated in vacuo. The residue is crystallized from ethanol and the crystals are further purified by trituration with ether and finally recrystallization 1,2,3 ,7, l 2, 1 2a-hexahydro-7- oximino pleiadene, m.p. l89.5-196C.

When the above process is carried out and a 1,2,3 ,l2a,-tetrahydro-5-methyl-7(12H)- pleiadenone, b. 5-chloro-l ,2,3,1 2a-tetrahydro-7( l2H)-pleiadenone,

c. 1,2,3 l 2a-tetrahydro-5-methoxy-7( 12H)- pleiadenone,

d. 1,2,3 ,4,13,13a-hexahydro-6-trifluoromethyl-8H- dibenzo[b,ef]heptalen-8-one,

6. 1,2,3 ,4,1 3 ,13a-hexahydro-8H-dibenzo[b,ef]heptalen-8-one,

f. 1,2,3 ,1Za-tetrahydro-l-trifluoromethyl-7( 12H pleiadenone, or

g. l0-chloro-1 ,2,3, 1 2a-tetrahydro-7( 12H )-pleiadenone is used in place of 1,2,3,12a-tetrahydro-7(12H)- pleiadenone, there is obtained:

a. 1,2,3,7,l2,12a-hexahydro--methyl-7-oximinopleiadene,

b. 5-chloro-l,2,3,7,12,l2a-hexahydro-7-oximinopleiadene 0. 1,2,3 ,7 ,12,l2a-hexahydro-5-methoxy-7-oximinopleiadene,

d. l,2,3,4,1 3 l 3a-hexahydro-8-oximino-6- trifluoromethyl-8H-dibenzo [b,ef]heptalen,

e. 1,2,3,4,13,13a-hexahydro-8-oximino-8H-dibenzo[b- ,ef]heptalen,

f. l ,2,3 l 2,1 2a-hexahydro-7-oximino-10-trifluoromethyl-pleiadene, or

g. 10-chloro-1,2,3,7,12,12a-hexahydro-7-oximinopleiadene, respectively.

EXAMPLE 6 1,2,3,7,12,12a-hexahydro-7-amino pleiadene A suspension of 17.5 g. 1,2,3,7,]2,12a-hexahydro-7- oximino pleiadene (0.067 mole) in 200 ml. ethanol is heated to reflux, at which time most of the solid is in' solution. The external heat is removed and 23 g. (1 mole) of sodium metal is added at a rate maintaining .a vigorous reflux for 1 hour. When all the sodium is consumed, the solvent is removed in vacuo. The residue is treated with chloroform and washed with water and a saturated sodium chloride solution, then dried over magnesium sulfate and evaporated in vacuo. The residue is crystallized from ethanol and recrystallized from chloroform-ethyl ether (1:1) to give l,2,3,7,12,1- 2a-hexahydro-7-amino pleiadene; m.p. 8486C.

When the above process is carried out and in place of 1 l,2,3,7,12,l2a-hexahydro-7-oximino pleiadene there is used the corresponding starting material desig- EXAMPLE 7 N-(1,2,3,7,l2,12a-hexahydro-7-pleiadyl)-N-methyl urea To a solution of 10.6 g. (0.043 mole) 1,2,3,7,12,12a-

hexahydro-7-amino pleiadene in 110 ml. tetrahydrob. N-(5-chloro-l,2,3,7,12,12a-hexahydro-7-pleiadyl)- N-methyl urea,

c. N-( l ,2,3,7,12,12a-hexahydro-5-methoxy-7- pleiadyl)-N-methyl urea,

d. N-(1,2,3,4,13,l3a-hexahydro-8-pleiadyl-6- trifluoromethyl-8H-dibenzo[b,ef]heptalen)-N- methyl urea,

e. N-(1,2,3,4,l3,13a-hexahydro-8-pleiadyl-8H- dibenzo[b,ef]heptalen)-N-methyl urea,

f. N-( 1 ,2,3 ,7 ,l 2, l2a-hexahydro-7-pleiadyl-10- trifluoromethyl-pleiadyl-N-methyl urea, or g. N-( l0-chloro-l,2,3,7,l2,12a-hexahydro-7-pleiadyl)- N-methyl urea, respectively.

EXAMPLE 8 1,2,3,7,12,12a-hexahydro-7-hydroxy pleiadene A solution of 33 g. (0.133 mole) l,2,3,12atetrahydro-7 (l2H)-pleiadenone in 360 ml. ethanol is cooled to 10 and 5.03 g. sodium borohydride is added portionwise. The reaction mixture is allowed to warm to room temperature and stirred there for'l7 hours. Then add a solution of m1. ethanol/25 ml. water and warm on a steam bath for 30 minutes, cool and evaporate the ethanol. The residue is dissolved in chloroform, washed with water and saturated in sodium chloride solution, then dried over magnesium sulfate and evaporated in vacuo. The residue is triturated in cold ethyl ether to give 1,2,3,7,12,l2a-hexahydro-7- hydroxy pleiadene; m.p. 118133C.

When the above process is carried out and in place of 1,2,3,12a-tetrahydro-7-(l2H)-pleiadenone there is used the corresponding starting materials designated as products (a-g) in Example 7, there is obtained a. 1 ,2,3,7,1 2,1 2a-hexahydro-S-methyl-7-hydroxy pleiadene,

b. 5-chloro-1,2,3 ,7,12,12a-hexahydro-7-hydroxy pleiadene,

c. 1,2,3 ,7, l 2, l 2a-hexahydro-5-methoxy-7-hydroxy pleiadene,

d 1,2,3,4,13 ,13a-hexahydro-8-hydroxy-6- e. l,2',3,4,1 3,1 3a-hexahydro-8-hydroxy-8H-dibenzo[b- ,ef]heptalen,

f. 1 ,2,3,1 2,12a-hexahydro-7-hydroxy-10- trifluoromethyl pleiadene, or

g. lO-chloro-l ,2,3 ,7, l 2,12a-hexahydro-7-hydroxy pleiadene, respectively.

EXAMPLE 9 1 ,2,3,7,l2,12a-hexahydro-7-chloro-pleiadene A solution of 12.2 g. (0.049 mole) 1,2,3,7,12,12ahexahydro-7-hydroxy pleiadene in 250 ml. benzene is 13 treated with gaseous HCl for 15 minutes, maintaining a temperature below 30C. The resulting solution is treated with calcium chloride, filtered and evaporated in vacuo and finally recrystallized from ethyl ether to give 1 ,2,3,7,12, l 2a-hexahydro-7chloro pleiadene; m.p. 135l37C.

When the above process is carried out and in place of 1,2,3 ,7,1 2,1 2a-hexahydro-7-hydroxy pleiadene there is used the corresponding starting materials designated as products (ag) in Example 8, there is obtained a. 1,2,3 ,7 ,12,12a-hexahydro--methyl-7-chloro pleiadene,

b. 5-chloro-l,2,3,7,12,12a-hexahydro-7-chloro pleiadene,

c. l,2,3,7,12,12a-hexahydro-5-methoxy-7-chloro pleiadene,

(1. 1,2,3 ,4,1 3 ,l 3a-hexahydro-8-chloro-6- trifluoromethyl-SH-dibenzo[b,ef] heptalen,

e. 1 ,2,3 ,4,13 ,13a-hexahydro-8-chloro-8H-dibenzo[b- ,ef]heptalen,

f. l ,2,3, 1 2,1 2a-hexahydro-7-chlorol O-trifluoromethyl pleiadene, or

g. -chloro-1 ,2,3 ,7,12,12a-hexahydro-7-chloro pleiadene, respectively.

EXAMPLE 1O 1 ,2,3,7, 1 2,1 2a-hexahydro-7-cyano pleiadene A suspension of 34.8 g. (0.26 mole) of silver'cyanide and 300 ml. bezene is warmed, in the dark, to 35 and a solution of 35 g. (0.13 mole) of l,2,3,7,l2,l2ahexahydro-7-chloro-pleiadene is added dropwise with stirring. The mixture is heated at reflux for 5 hours and filtered while hot. The solvent is evaporated in vacuo and the residue crystallized by trituration with ether and recrystallized from hot ethyl acetate to give l,2,3,- 7,12, l 2a-hexahydro-7-cyano-pleiadene; l52-l 56C When the above process is carried out and in place of l,2,3,7,12,12a-hexahydro-7-chloro pleiadene there is used the corresponding starting materials designated as product (ag) in Example 9, there is obtained a. l,2,3,7,12,12a-hexahydro-5-methyl-7-cyano pleiadene,

b. 5-chloro-1,2,3,7,l2,12a-hexahydro-7-cyano pleiadene,

c. 1,2,3,7,]2,12a-hexahydro-5-methoxy-7-cyano pleiadene,

d 1,2,3,4,l3,13a-hexahydro-8-cyano-6- v e. l,2,3,4,l3,13a-heXahydro-8-cyano-8H-dibenzo[b-- ,ef]heptalen, f. 1,2,3 ,1 2,12a-hexahydro-7-cyano-IO-trifluoromethyl pleiadene, or g. l0-ch1oro-l,2,3,7,12,l2a-hexahydro-7-cyano pleiadene, respectively.

EXAMPLE 11 1,2,3 ,7 ,l2,12a-hexahydro-7-carboxamido-pleiadene A stream of boron trifluoride is passed over a suspension of 12.95 g. (0.05 mole) l,2,3,7,l2,12a-hexahydro- 7-cyano pleiadene and 60 ml. acetic acid and 11 ml. water until saturated. The temperature rose to l35-l45C. and is maintained there for 15 minutes by external heating. The mixture is cooled in ice and made basic by the addition of 6N NaOH. The resulting precipitate is filtered, washed with water, dissolved in chloroform and dried over magnesium sulfate and then evaporated in vacuo. The residue is crystallized from ether and recrystallized from ethanol to give l,2,3,7,l- 2,12a-hexahydro-7-carboxamido-pleiadene; m .p. l99.5-201C.

When theabove process is carried out and in place of l,2,3,7,l2,l2a-hexahydro -7-cyano pleiadene there is used the corresponding starting designated as product (ag) in Example 10 there is obtained a. l ,2,3 ,7,12,l2a-hexahydro-5-methyl-7-carboxamido pleiadene,

b. 5-chloro-l,2,3,7,12,12a-7-carboxamido pleiadene,

c. 1,2,3 ,7 ,12,12a-hexahydro-5-methoxy-7- carboxamido pleiadene,

d. 1,2,3,4,13,13a-hexahydro-8-carboxamido-6- trifluoromethyl-SH-dibenzo[b,ef]heptalen,

e. 1,2,3 ,4,13 ,13a-hexahydro-8-carboxamido-8l-ldibenzo[b,ef]heptalen,

f. 1,2,3 ,7,12,12a-hexahydro-7-carboxamido-10- trifluoromethyl pleiadene, or g. l0-chloro-l ,2,3,7, 1 2, l 2a-hexahydro-7-carboxamido pleiadene, respectively. 1

What is claimed is:

l. A compound of the formula wherein n represents lor 2;

R represents H, halo having an atomic weight of 19,-36, or trifluoromethyl; and

R represents H, Halo having an atomic weight of 19-36, trifluoromethyl, straight chain lower alkyl, or straight chain lower alkoxy.

2. The compound of claim 1 which is l,2,3,7,l2,l2a-

hexahydro-7-cyano pleiadene. 

1. A COMPOUND OF THE FORMULA
 2. The compound of claim 1 which is 1,2,3,7,12,12a-hexahydro-7-cyano pleiadene. 